Apparatus and method for delivering therapeutic and diagnostic agents

ABSTRACT

The present invention provides an drug-delivery tool and method for delivering a selected diagnostic or therapeutic agent to a target site within a selected body tissue, such as the myocardium of the heart. In one embodiment, the drug-delivery tool is configured to be introduced percutaneously for intravascular delivery into temporary cavities formed in the myocardium from the epicardial surface. In another embodiment, the drug-delivery tool is configured for intraoperative use, to be introduced thoracoscopically or through a thoracotomy, to form temporary cavities in the myocardium from the epicardial surface. The drug-delivery tool generally comprises an accessing device having a tissue-penetrating implement in its distal-end region, and means for delivering a selected agent in a cavity formed by the implement. In an exemplary use, wherein a patient&#39;s heart is treated with an agent for transferring genetic information to the heart tissue, the distal end of the accessing device is conditioned adjacent a selected region of the heart wall, and the tissue-penetrating implement is advanced to form a temporary channel in the myocardium. The gene-therapy agent is introduced into the cavity by the delivery means and retained therein by means overcoming the intra-myocardial pressures. In one embodiment, the treated tissue is stunned, ischemic or hibernating organ tissue that has at least partially lost its normal capillary ability at natural vasomotion.

[0001] This application claims benefit of U.S. Provisional PatentApplication No. 60/133,179 filed May 7, 1999, which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention is directed to an drug-delivery tool andmethod of delivering selected therapeutic and/or diagnostic agents totarget sites in selected body tissues. More particularly, the inventionprovides for the creation of temporary cavities in desired layers of aselected tissue, for example, myocardial tissue of the heart, and forthe delivery of one or more selected agents therein.

BACKGROUND OF THE INVENTION

[0003] Intra-muscular needle injection of therapeutic compounds is wellknown in the medical arts, as is intra-coronary injection wherepre-existing intra-coronary arteries provide perfusate conduits. Inheart disease, the existing coronary artery in-flows to capillary bedsis often compromised. Newly developed gene and protein therapeuticagents hold promise in their ability to act on the surviving smallercapillary beds to grow and expand them. As has been witnessed, theintra-myocardial cellular lattice limits angiogenic response to about5-10 mm and similar limits occur with direct needle injections instunned or ischemic heart tissue. The physician must work within anenvironment of compromised capillary bed vascularity. Physicians arefurther limited to some degree by drug viscosity—where the drugviscosity is too low, rapid wash-out can occur; and where too high,capillary occlusion can occur—as well as by high infusate pressureinduced cellular damages. These problems are not typical of commonhealthy muscle tissue injections in the arm or leg. The prior artteaches the creation of permanent channels with the use of lasers, radiofrequency heating and mechanical cutting means. Such channels oftencompromise the capillaries that are sought to be accessed with a drug,wash out readily, and resolve ultimately as fibrous connective scartissue. Needle and membrane tools may improve access to capillaries butoffer no stretching forces and don't offer unobstructed capillaryaccess.

SUMMARY OF THE INVENTION

[0004] One embodiment of the invention provides a drug-delivery tool fordelivering a drug to an internal member of a tissue, such as aheart-wall. The tool comprises an accessing device having distal andproximal ends, an inner lumen extending therebetween, a drug-deliveryreservoir adapted to hold such drug, and a user-control structure at theaccessing device's proximal end. The tool further includes atissue-penetrating implement carried at the accessing device's distalend for axial movement into and out of the lumen. The implement hasfirst and second expandable members which are disposed in asubstantially co-extension condition, when the implement is disposed ina retracted condition within the lumen. Alternatively, the implement mayassume an expanded, spaced-apart condition when the implement isadvanced to an extended condition out of the lumen. At least one of themembers has a tip for penetrating such tissue. A first operativeconnection exists between the control structure and the implement thatis operable, upon user activation of the control structure, to advancethe implement from its retracted to its extended condition. When theaccessing device's distal end is placed against a surface region of thetissue, the implement is advanced into the tissue, causing the twoexpandable members to expand to form a cavity within the tissue. Asecond operative connection exists between the control structure and thereservoir that is operable, upon user activation of the controlstructure, to deliver drug from the reservoir into such cavity.Placement of the accessing device's distal end against a surface regionof such tissue, and activation of the control structure results in thedelivery of drug into a cavity within the tissue.

[0005] In another embodiment, the implement includes at least twoexpandable elements which move away from one another as the implement isbeing advanced, from its retracted to its extended condition, into suchtissue, to form a cavity in the tissue.

[0006] In yet another embodiment, the second expandable member of thetissue-penetrating implement defines a lumen having a plurality ofopenings that permit direct communication of an drug passed into acavity formed by the tool with at least about 90% of the surface area ofthe tissue directly bordering the drug receiving space.

[0007] In a particularly preferred embodiment, the accessing device is aflexible catheter accessing device; and further comprises a pull-wireassembly extending longitudinally through the catheter accessing device,the pull-wire assembly being operable to deflect the distal end of theaccessing device substantially within a plane; and one or more forcecontact transducers mounted at the distal end of the accessing devicewithin the deflection plane. This embodiment may further comprise one ormore additional force contact transducers mounted at the distal end ofthe accessing device outside of the deflection plane.

[0008] In another embodiment, the first expandable member furthercomprises construction from a shape memory material capable of a firstremembered curved shape, and a second, stress induced linear shapecausing the first expandable member to cut in an arc shape as it isadvanced through a tissue upon extension from the confines of theaccessing device lumen.

[0009] In still another embodiment, the second expandable membercomprises a ribbed balloon, wherein each rib defines a lumen in fluidcommunication with the drug-delivery reservoir, and each rib furtherdefines a plurality of exit ports from the rib lumen that the drug mayperfuse through into the formed cavity.

[0010] In another embodiment, the first expandable member is formed in acork-screw shape tubular member defining a lumen within exiting at anend distal to the accessing device and in communication with thedrug-delivery reservoir, the first expandable member is rotatable alongits axis to permit it to screw into a tissue upon axial rotation, andupon stopping axial rotation, withdraw into the lumen of the accessingdevice thereby pulling the tissue up into the lumen of the accessingdevice until such tissue is sealably urged against the accessingimplement's lumen edge causing a seal to form between the accessingimplement's lumen edge and the tissue, and further causing a cavity toform between the distal region of the first expandable member and thetissue adjacent to that region.

[0011] In one embodiment, some of the expandable members of thetissue-penetrating implement define lumens with a plurality of openingsin fluid communication with the drug-delivery reservoir such that a drugmay be introduced into a formed cavity with at least about 90%, andpreferably greater than about 95%, of the surface area of the tissuedirectly bordering the cavity.

[0012] The accessing device can be, for example, a flexible catheteraccessing device or the accessing device of an endoscope-type tool. Inan embodiment of the former (i.e., a catheter-type tool), the toolfurther includes (i) a pull-wire assembly extending longitudinallythrough the catheter accessing device, with the pull-wire assembly beingoperable to deflect a distal-end region of the accessing devicesubstantially within a plane; and (ii) one or more (for example, two)ultrasound or force contact transducers mounted on opposing sides of theorifice at the distal end of the accessing device within the deflectionplane. Optionally, one or more (for example, two) additional transducerscan be mounted at the distal end of the accessing device outside of thedeflection plane.

[0013] One aspect of the present invention provides an drug-deliverytool for delivering a selected diagnostic or therapeutic agent to atarget site within a selected body tissue, such as myocardial tissue ofthe heart. Generally, the drug-delivery tool includes an accessingdevice having proximal and distal ends, with a lumen extending betweensuch ends and terminating at an orifice at the distal end. Atissue-penetrating implement is movable between a retracted condition,within a distal region of the lumen, and an extended condition,extending out of the orifice. The tissue-penetrating implement includesa tip configured to penetrate a selected body tissue when (i) the distalend of the accessing device is placed thereagainst and (ii) theimplement is advanced from its retracted condition to its extendedcondition. In addition, the tissue-penetrating implement includes afirst expandable member, disposed proximal of the tip, for following thetip to a target site as the tip penetrates the selected tissue. A secondexpandable member, also proximal to the tip of the implement, is adaptedto expand radially as the implement is advanced to its extendedcondition, with a force sufficient to form a cavity at the target siteby pressing the tissue adjacent the penetration site away from thelongitudinal axis of the implement. An agent-delivery passage or conduitextends longitudinally through at least a member of the accessingdevice, with a distal end of the passage defining an exit port facingthe expandable member of the tissue-penetrating implement. By thisconstruction, an agent, passed or drawn through the passage and out ofthe exit port, is directed into a central region of the expandablemember, and any cavity formed thereby.

[0014] In one embodiment, the tissue-penetrating implement of thedrug-delivery tool includes (i) a cutting or slicing tip at itsdistal-end region, and (ii) one or more resiliently flexible expandablemembers extending proximally therefrom, with the expandable membersbeing adapted to expand radially outward in their normal state. Theexpandable members can be, for example, wires or filaments made ofNintinol, or the like. Movement of the tissue-penetrating implement canbe effected using an actuation line attached at one end to a proximalend of the implement and attached at its other end to a manuallyoperable deflection mechanism at a proximal end of the drug-deliverytool. By this construction, sliding movement of the line within theaccessing device is transmitted to the implement—causing the implementto move.

[0015] The agent-delivery passage of the drug-delivery tool can beformed, for example, by an elongate conduit having an internal lumenthat extends between the proximal end of the accessing device and adistal-end region of the accessing device. In one embodiment, such aconduit is adapted for sliding movement within the accessing device,coupled with movement of the tissue-penetrating implement.

[0016] One embodiment of the drug-delivery tool, particularly useful fordelivering a selected agent having a net negative charge (for example,DNA), further comprises first and second electrodes adapted to be placedin electrical communication with a power supply. The first electrode, inthis embodiment, is disposed at a distal region of thetissue-penetrating implement and the second electrode is disposedproximally of the implement. Generation of a positive charge at thefirst terminal is effective to draw at least a portion of the negativelycharge species from a supply or holding reservoir, through theagent-delivery passage, and into the expandable member of thetissue-penetrating implement.

[0017] Another embodiment of the drug-delivery tool is particularly wellsuited for placing a solid or semi-solid agent in a cavity formed by thecavity forming implement and then permitting the agent to move outwardlyas portions of it dissolve or otherwise slough off. In one particularconstruction, the expandable member of the tissue-penetrating implementincludes a plurality of resiliently flexible expandable members (forexample, wires or filaments of Nintinol, or the like) disposed at spacedpositions about the longitudinal axis of the implement so as to define acage or skeleton capable of holding the agent as it is placed in acavity formed by the implement. The cage is provided with open regionsbetween its expandable members sufficient to provide direct exposure ofthe agent to at least about 95% of the tissue bordering the cavity.

[0018] Another general embodiment of the drug-delivery tool of theinvention includes (i) an accessing device having proximal and distalends, with a lumen extending therebetween and terminating at an orificeat the distal end; (ii) a tissue-penetrating implement movable between aretracted condition, within a distal region of the lumen, and anextended condition, extending out of the orifice; with the implementincluding (a) a tip configured to penetrate a selected body tissue whenthe distal end of the accessing device is placed thereagainst and theimplement is moved from its retracted condition to its extendedcondition, and (b) a cage member disposed proximal of the tip forfollowing the tip to a target site within such tissue, and adapted toassist in the formation and maintenance of a cavity at the target siteby pressing the tissue at the target site away from the longitudinalaxis of the implement as it is inserted therein and having sufficientrigidity to resist inwardly directed forces of the tissue tending tocollapse the cavity; and (iii) an agent-delivery passage extendinglongitudinally through at least a member of the accessing device, with adistal end of the passage defining an exit port facing the cage memberfor directing a selected agent, passed through the passage, into acentral region of the cage member and any such cavity formed thereby.

[0019] The cage member can comprise, for example, a plurality ofexpandable elements disposed about the central, longitudinal axis of theimplement, with open regions between adjacent expandable members.Preferably, at least about 95% of the cage member is open. The cagemember can be expandable (tending to flex outwardly), or generallynon-expandable.

[0020] In another of its aspects, the present invention provides amethod for delivering a selected diagnostic or therapeutic agent to atarget site within a selected body tissue.

[0021] According to one general embodiment, the method includes thesteps of:

[0022] (i) forming a cut or slice extending from a wall of the selectedtissue to the target site;

[0023] (ii) moving or pressing the tissue bordering the cut or sliceradially outward, thereby forming a cavity within the tissue at thetarget site;

[0024] (iii) delivering a selected agent into the cavity, with thecavity being maintained; and

[0025] (iv) permitting the cavity to collapse once a selected amount ofthe agent has been delivered therein.

[0026] In one embodiment, at least about 90% (and preferably greaterthan 95%) of the surface area of the tissue bordering the cavity isdirectly exposed to the cavity, so that the agent delivered into thecavity can pass directly into the exposed tissue.

[0027] Step (i) of the method (i.e., cutting/slicing) is preferablyeffected using a cutting or slicing implement, such as a blade edge ortip, that is configured to avoid the removal of tissue along the regionof the cut or slice beyond the inherent cellular injury due to thecutting or slicing.

[0028] According to one embodiment, the cut or slice formed in step (i)is made along a substantially linear axis, with the axis being orientedgenerally normal to the wall of the selected tissue. Ultrasound can beused to achieve such orientation.

[0029] The agent can be delivered using, for example, an elongateagent-delivery conduit defining a passage or lumen terminating at adistal orifice through which the agent can exit. Preferably, duringdelivery of the agent using such a tool, the orifice does not makesubstantial contact with the selected tissue, thereby maximizing thetissue surface area available for contact with the agent.

[0030] In one embodiment, the selected tissue is heart tissue (forexample, myocardial tissue), and the cut or slice is formed from anendocardial wall, a septal wall, or an epicardial wall.

[0031] In another embodiment, the selected tissue is stunned, ischemicand/or hibernating organ tissue that has at least partially lost itsnormal capillary ability at vasomotion. The greater surface area andcapillary access provided by practicing the present invention permitsthe agent to be moved through micro-capillaries even where assistance bynatural vasomotion is greatly diminished or unavailable.

[0032] A wide variety of agents can be delivered using the presentinvention. The selected agent can be, for example, an angiogenic agent(for example, a protein and/or nucleic acid). In one embodiment, theagent is a nucleic acid, for example, naked DNA, intended for deliveryto heart tissue.

[0033] A further aspect of the present invention provides a method wherethe normal pressure drug tissue treatment area of 5-10 mm obtained withdirect needle injection or TMR can be improved upon by creating atemporary cavity having significantly greater direct capillary accessdue to surface area, lack of non-perfusing delivery implement to cellcontact patches and implement stretching force.

[0034] These and other features and advantages of the present inventionwill become clear from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The structure and manner of operation of the invention, togetherwith the further objects and advantages thereof, may best be understoodby reference to the following description taken in conjunction with theaccompanying drawings, in which:

[0036]FIG. 1 is an elevational view of a steerable catheter assembly,with its distal end region enlarged and in section showing atissue-penetrating implement therein, as taught by an embodiment of thepresent invention;

[0037]FIG. 2 is a side sectional view showing two angle-mountedultrasound transducers on the distal end of a steerable catheteraccessing device, in accordance with an embodiment of the presentinvention;

[0038]FIG. 3 is a cross sectional view of the catheter assembly shown inFIG. 1, taken laterally across a mid-member of the catheter accessingdevice;

[0039]FIG. 4 is a side sectional view of the catheter-assemblydistal-end region of FIG. 1, taken longitudinally therealong, with thetissue-penetrating implement inserted into a selected tissue to form acavity therein for receiving a selected agent;

[0040]FIG. 5A illustrates a section of normal myocardial tissue;

[0041]FIG. 5B illustrates a section of myocardial tissue with atemporary cavity formed therein;

[0042]FIG. 6 is a side elevational view, with members shown in crosssection, of an endoscope-type agent delivery tool having atissue-penetrating implement like that of the catheter assembly of FIG.1;

[0043] FIGS. 7(A)-7(C) illustrate an accessing device, shown in section,with a movable implement for forming a cavity in a selected tissue anddelivering a selected agent therein, in accordance with the teachings ofone embodiment of the present invention; and,

[0044] FIGS. 8(A)-8(C) illustrate an accessing device, shown in section,with a movable implement for forming a cavity in a selected tissue andplacing a selected agent therein, in accordance with an embodiment ofthe present invention.

[0045] FIGS. 9(a-d) depict an embodiment having a force contacttransducer.

[0046] FIGS. 10(a-b) depict a corkscrew shaped expandable memberembodiment.

[0047] FIGS. 11(a-c) depict a balloon expandable member embodiment.

[0048] FIGS. 12(a-c) depict an arc cutting embodiment.

DETAILED DESCRIPTION OF THE INVENTION

[0049] The following discussion of the preferred embodiments of thepresent invention is merely exemplary in nature. Accordingly, thisdiscussion is in no way intended to limit the scope of the invention.

[0050] An exemplary drug-delivery tool which embodies various featuresof the invention is shown in FIGS. 1 through 4. As will become apparent,the illustrated drug-delivery tool is particularly well suited forpercutaneous introduction into a subject for intravascular delivery of aselected agent into temporary cavities formed in a desired layer of aselected tissue. With initial reference to FIG. 1, a catheter assembly(which may be disposable, in whole or in part), indicated generally bythe reference numeral 12, includes a control structure (hand unit) 14attached to a steerable catheter accessing device 16 having acontrollably deflectable distal-end member. Steering of the catheterassembly can be accomplished in a variety of ways. For example, thecatheter assembly can include steering components like those disclosedin U.S. Pat. No. 5,876,373, entitled “Steerable Catheter,” to Giba etal.; and/or in co-pending U.S. Provisional patent application Ser. No.09/080,175 filed May 16, 1998, entitled, “Drug Delivery Module,” toGlines et al.; and/or in published European Patent Application No. EP 0908 194 A2, each of which is expressly incorporated herein by reference.Briefly, in the illustrated embodiment, a pull wire 18, having anenlarged head member 18 a at its distal end, extends from the tip ofcatheter accessing device 16, through a wire-guide channel 19 extendingthrough catheter accessing device 16, to control structure (hand unit)14, whereat the wire's proximal end is coupled to a deflection orsteering actuator assembly. Rotation of a deflection knob 20, which isthreadedly mounted along a forward end of the hand unit, causes the pullwire to be pulled backward, or the catheter accessing device to bepushed forward, relative to one another, thereby inducing deflection ofthe distal end of the steerable catheter accessing device. Rather thanrunning the pull wire through a channel extending through the catheteraccessing device, another embodiment provides the pull wire extendinglongitudinally along the interior wall of the catheter accessing device(FIG. 3). Other steering mechanisms and arrangements, suitable for useherein, will be apparent to those skilled in the art. In yet anotherpreferred embodiment, the catheter is further guided by a coaxial secondcatheter as described in co-pending application U.S. Ser. No. 09/052,971and PCT publication WO 9949773A2 titled “Delivery catheter system forheart chamber” by Payne, filed Mar. 31, 1998, both herein incorporatedin their entireties by reference.

[0051] Catheter accessing device 16 is dimensioned to be placed in thevasculature of a subject and steered therethrough until the tip isdisposed adjacent a selected region of tissue, for example, a surface orwall within a heart chamber (such as against the endocardial wall withinthe heart's left ventricle).

[0052] Visualization enhancement aids, including but not limited toradiopaque markers, tantalum and/or platinum bands, foils, and/or stripscan be placed on the various components of drug-delivery tool-catheterassembly 12, including on the deflectable end member of catheteraccessing device 16. In one embodiment, for example, a radio-opaquemarker (not shown) made of platinum or other suitable radio-opaquematerial is disposed adjacent the tip for visualization via fluoroscopyor other methods. In addition, or as an alternative, one or moreultra-sonic transducers can be mounted on the catheter accessing deviceat or near its tip to assist in determining its location and/orplacement (for example, degree of perpendicularity) with respect to aselected tissue in a subject, as well as to sense wall contact with,and/or wall thickness of, the tissue. Ultra-sonic transducer assemblies,and methods of using the same, are disclosed, for example, in publishedCanadian Patent Application No. 2,236,958, entitled, “Ultrasound Toolfor Axial Ranging,” to Zanelli et al., and in co-pending U.S. patentapplication Ser. No. 08/852,977, filed May 7, 1997, entitled,“Ultrasound Tool for Axial Ranging,” to Zanelli et al., each of which isexpressly incorporated herein by reference. In one embodiment of thepresent invention, depicted in FIG. 2, two transducers, denoted as 26and 28, are angle mounted at the tip of catheter accessing device 16 inthe axis of pull-wire deflection. This construction permits an operatorto determine, by comparing signal strength, whether the catheter tipregion is perpendicular to a selected tissue surface or wall.Additionally, this two-transducer arrangement provides an operator withinformation useful for determining an appropriate adjustment directionfor improving perpendicularity, as compared to single-transducerarrangements that, while capable of indicating perpendicularity bysignal strength amplitude, are generally incapable of indicating asuitable direction in which to move the tip to improve perpendicularity.In a related embodiment, third and fourth transducers (not shown) areadded, off of the deflection axis, to aid an operator with rotationalmovement and rotational perpendicularity in the non-deflecting plane ofthe subject tissue surface. Each of the above ultrasound transducers maypreferably be substituted with force contact transducers described inco-pending U.S. patent application Ser. No. 60/191,610 by C. Tom titled“Apparatus and method for affecting a body tissue at its surface”, filedMar. 23, 2000, [Attorney docket 5756-0011] herein incorporated byreference. An additional benefit of using a force contact transducer isthat the contact force and incident angle are know to the user enablingthe user to achieve a seal between the distal end of the accessingdevice and a tissue such that a seal is formed between the twopreventing administered drug from seeping out of a formed cavity.

[0053] In some preferred embodiments, one or more elongate lumens mayextend between the proximal and distal ends of the catheter accessingdevice, with (i) at least one lumen being dimensioned to accommodate acavity forming implement for axial movement along a region of theassembly's distal end, and (ii) at least one lumen being configured topermit passage of one or more selected therapeutic and/or diagnosticagents from an agent-supply region (for example, a reservoir in the handunit) to, and out of, a terminal orifice at the assembly's distal end.The just-described items (i) and (ii) can be achieved using a singlelumen, or multiple lumens. In one embodiment, for example, catheteraccessing device 16, as depicted in FIG. 1, is preferably formed with anouter diameter of between about 2.25 to 2.75 mm (preferably 7 French),and an inner diameter, defining a primary lumen 22, of about 1 mm. Atits distal end, lumen 22 terminates at an orifice 24. Atissue-penetrating implement 48 (described below) is adapted formovement within a distal-end region of lumen 22. A selected agent can bepassed through the main lumen directly, i.e., in contact with the mainlumen's interior walls, and/or indirectly, for example, using one ormore additional lumens (for example, sub-lumens) extending coextensivelyand/or coaxially with the main lumen. An embodiment of the latterconstruction is also illustrated, in part, in FIGS. 3 and 4. Forexample, FIGS. 1, 3, and 4 each depict different aspects of an elongate,flexible agent-delivery conduit 30 is disposed substantially coaxiallywithin catheter accessing device 16, extending from control structure(hand unit) 14 to a distal region of lumen 22. Conduit 30 can be formed,for example, of a substantially inert polymeric material that resistscollapse during bending or twisting, such as braided polyimide, braidedPEBAX, or the like. Conduit 30 defines a hollow, axial lumen or passage32, having a diameter within a range of from about 0.25 mm to about 1 mm(for example, about 0.5 mm), or from about 0.010″ to about 0.040″ (forexample, about 0.020″), that communicates at its proximal end with anagent-supply reservoir disposed in control structure (hand unit) 14, andterminates at its distal end at an exit or infusion port 34, throughwhich a selected therapeutic and/or diagnostic agent can pass. Asdescribed below, conduit 30 is adapted for reciprocal sliding movementwithin catheter accessing device 16 and, thus, is provided with an outerdiameter less than the inner diameter of catheter accessing device 16,for example, about 1 mm or less in certain constructions.

[0054] At this point, certain details of the hand unit relating to agentstorage and dispensing will be described, bearing in mind thatadditional details are set forth in co-pending U.S. Provisional PatentApplication Ser. No. 09/080,175 filed May 16, 1998, entitled, “DrugDelivery Module,” to Glines et al., incorporated herein by reference. Inone preferred embodiment depicted in FIG. 1, control structure (handunit) 14 is provided with a fixed drug-delivery reservoir for holding asupply of a selected agent to be dispensed. In this embodiment, a supplyvessel, such as syringe 36, can communicate with the drug-deliveryreservoir via a connector provided in the unit's outer housing 38. Theconnector is preferably a substantially sterile connector, such as astandard Luer-type fitting or other known standard or proprietaryconnector. In another embodiment, the supply reservoir comprises asyringe, pre-loaded with a selected agent, that can be removably fitinto a holding area inside the housing. In both such embodiments, adosage volume adjustment thumbscrew 40 can be mounted in the housing 38so as to be externally accessible for accurate, local and rapid dosagevolume adjustment. Also, a dosage volume scale or indicator, as at 42,can be provided in the housing 38. Upon depressing a trigger mechanism44 along one side of control structure (hand unit) 14, manually orotherwise, the agent stored in the drug-delivery reservoir moves intoconduit 30. It should also be noted that trigger mechanism 44 is coupledto the proximal end of conduit 30 such that, upon being depressed, theconduit is pushed forward (advanced) within catheter accessing device 16from a normal, retracted condition, depicted in FIG. 1, to a dispensingcondition, shown in FIG. 4, whereat conduit orifice 34 can be positionedclosely adjacent a selected tissue, such as 46, against whichcatheter-accessing device orifice 24 has been placed. Upon releasing thetrigger mechanism, conduit 30 shifts back to its normal condition. Thedistance traversed by conduit 30, in each direction, is from about 2 toabout 10 mm, and preferably about 5 mm.

[0055] A tissue-penetrating implement, indicated generally as 48, isalso longitudinally movable within catheter accessing device 16, betweena retracted condition, within a distal region of lumen 22 (FIG. 1), andan extended (advanced) condition, passed through and extending out oforifice 24 (FIG. 4), over a stroke of about 4-6 mm, and preferably about5 mm. Movement of implement 48 is effected by way of an elongateactuation line 50, depicted in cross-section in FIG. 3, operativelycoupled at one end to trigger mechanism 44 (FIG. 1) and extendingaxially through conduit 30 from control structure (hand unit) 14 to aproximal end of implement 48. Preferred materials for forming theactuation line are laterally flexible, permitting movement throughtortuous pathways, and sufficiently incompressible along thelongitudinal direction to provide for the efficient transmission ofmotion from the proximal end to the distal end. Suitable materialsinclude, for example, stainless steel or a braided composite. Inoperation, upon the depressing trigger mechanism, implement 48 isshifted from its normal, retracted condition to its extended condition,and upon release of the trigger mechanism, implement 48 returns to itsretracted condition.

[0056] For reasons that will become apparent below, it should be notedthat the above-described advancement of both conduit 30 and cuttingimplement 48 takes place substantially simultaneously (i.e., thesemotions are coupled) with a single depression of trigger mechanism 44.In addition, optionally, with the same trigger depression, an agent heldin a reservoir in the hand unit is dispensed from conduit 30.Preferably, such dispensing is effected immediately after (not before)the conduit and cutting implement have reached their respective extendedconditions. For example, the initial depression can actuate axialmovement of the conduit and cutting implement, and the latter member ofthe depression can effect dispensing. Similarly, both conduit 30 andcutting implement 48 are retracted together with release of the triggermechanism, and the dispensing of the selected agent is stopped.

[0057] With further regard to the tissue-penetrating implement 48, itsdistal end includes a cutting or slicing tip, denoted as 52. In theillustrated arrangement, tip 52 takes the form of a narrow, three-sidedpyramid-like structure that tapers to a sharp point. Alternatively, tip52 could taper to a two-sided knife edge or blade, or any other suitablecutting or slicing structure. Preferred cutting or slicing structuresare configured to substantially avoid the removal of tissue beyond thecellular injury inherent in cutting.

[0058] Implement 48 further includes an expandable member, proximal oftip 52, comprised of one or more resiliently flexible expandableelements or expandable members, three of which are visible (out of atotal of four) at 54 in the embodiment of FIGS. 1 and 4. The expandablemembers are arranged at spaced positions about the implement'slongitudinal axis, and configured to flex outwardly, away from suchaxis, to collectively form a three dimensional support skeleton or cage.The expandable members can be, for example, narrow, elongate wires,filaments or ribbons, formed of a substantially inert, resilientlyflexible material, such as a metal or metal alloy (for example,stainless steel, nickel-titanium, or similar material) or from aninjection molded plastic. The distal end of each expander is turnedinward and attached to the proximal side of tip 52. When the expandablemember is disposed at its retracted condition (FIG. 1), the expandablemembers are compressed toward the implement's longitudinal axis; andwhen advanced to its extended condition (FIG. 4), the expandable membersare allowed to flex outward, so that, overall, the expandable memberachieves a maximum diameter of about 1-3 mm, and preferably from about1.75 mm to about 2 mm.

[0059] According to one preferred construction of the expandable member,between about 3-10 nickel-titanium (for example, as availablecommercially under the name “Nintinol”) filaments, each between about4-5 mm in length and from about 0.003″ to about 0.005″ in diameter areemployed as expandable members. The particular number, dimensions, andmaterial composition of the expandable members are not critical,provided only that the expandable members are capable of forming acavity when inserted into a selected tissue (i.e., they have sufficientstrength and spring capabilities), and, when in the expanded condition,a drug or other agent delivered into the region within the expandablemembers can move outwardly into the tissue about the cavity, with verylittle interference presented by the expandable members themselves, asshown in FIG. 4 with agent 58 in cavity 60. Regarding the latter, theexpandable members preferably occupy no more than about 10%, and morepreferably less than about 3%, of the region defining the boundarybetween the cavity and the target tissue thereabout. In this way, thevast majority of the tissue boarding a cavity can be directly exposed toan agent delivered into the cavity.

[0060] An exemplary method of using the above catheter assembly will nowbe described, wherein the catheter assembly is used for intra-myocardialdelivery of a selected therapeutic and/or diagnostic agent. Initially,catheter accessing device 16 is percutaneously introduced via femoral orradial artery access. This can be accomplished, for example, by way ofthe Seldinger technique (Acta Radiologica, 38, [1953], 368-376;incorporated herein by reference), a variation thereof, or otherconventional technique. Optionally, a conventional guiding or shieldingcatheter (not shown) can be employed to assist in tracking the cathetertool through the patient's vasculature and into targeted regions of theheart. Once arterial access is established, the catheter accessingdevice 16 is slid across the aortic valve and into the left ventriclechamber. The distal end of the catheter accessing device 16 ismaneuvered so as to be substantially perpendicular to the endocardialwall 46 (FIG. 4), using fluoroscopic visualization and/or ultrasoundguidance, and pressed thereagainst. Trigger mechanism 44 is nextdepressed, causing cutting tip 52 to advance into the myocardial tissue,in the direction of arrow 64, to a pre-set or adjustable depth.Expandable members 54 follow cutting tip 52 into the myocardium andexpand radially (for example, in the direction of arrows 66), creating acavity about the axis of penetration (i.e., the axis of cutting orslicing). Once the cavity has been created, the expandable members serveto maintain the cavity by resisting heart contractile forces. The sametrigger depression serves to deliver a selected agent through conduit 30into the cavity 60. After allowing the agent to enter into thesurrounding tissue for appropriate period of time, for example,typically less than about 2 minutes, the tissue-penetrating implement iswithdrawn, at which point the cavity can close.

[0061] Healthy myocardial tissue is illustrated in FIG. 5A. As shown,healthy tissue contains capillaries 70, interstitial tissue 72, andheart muscle cells 74 (See, for example, “Gray's Anatomy” (1959) at page597). FIG. 5B shows how a temporary cavity 60 can be created to directlyaccess, for example, along the direction of arrows 68, more capillaries70, more heart muscle cells 74, and tissue surface area 76. It should beappreciated that the creation of temporary cavities, as taught therein,provides direct access to a greater number of capillaries than has beenpossible by the prior techniques. As a result, the performance of theinfusate tool is greatly enhanced.

[0062] It is believed that abrasion to the wall of the cavities may aidin absorption of the agent. Accordingly, it may be desirable toconfigure the cutting tip and/or cavity expandable members of theinvention so as to allow selective abrasion. This can also beaccomplished, for example, by RF, thermal, acidic and/or ultrasonicmeans acting on the cutting tip and/or cavity expandable members.

[0063] It is noted that the above-described method is exemplary innature. Those skilled in the art will appreciate that the presentinvention provides for the delivery of selected agents to a wide varietyof body organs and regions.

[0064] Another embodiment of the drug-delivery tool of the presentinvention is shown in FIG. 6, wherein the tool is embodied in anendoscope-type tool, shown generally at 80. As described next, thedrug-delivery tool of this embodiment is configured for intraoperativeuse, to be introduced thoracoscopically or through a thoracotomy, toform temporary cavities in a selected tissue. The tool includes aproximal handpiece 82 (similar to the previously-described controlstructure (hand unit) 14) adapted to accommodate an drug-deliveryreservoir syringe 84, and a depressible trigger mechanism 86. Thisparticular surgical tool incorporates a reusable 5 mm thoracoscopiccamera 88 axially mounted to provide an operator with a field of view 90through lens 92. This allows the operator to work through a commonTrocar access port 94 placed, for example, through a patient's chestwall 96. In an exemplary use, upon traversing the epicardial surface 98of the heart, a tissue-penetrating implement 48, substantially asdescribed above, can create a temporary cavity for receiving a selectedagent. As with the catheter assembly, the tool is adapted to permit auser to both extend the tissue-penetrating implement and dispense a drugor other agent, with a single depression of the trigger mechanism 86.Additional details of the handpiece are presented in co-pending U.S.Provisional Patent Application Ser. No. 09/080,175 filed May 16, 1998,entitled, “Drug Delivery Module,” to Glines et al., incorporated hereinby reference. One skilled in the art would recognize that the abovementioned endoscopic embodiment may further be adapted for use withoutan endoscopic port, for example, such as in open surgery. Such anembodiment may be guided with or without visualization aids such as anoptical endoscope or other optical enhancement device.

[0065] It should be noted that, especially when used in open surgery,the tissue-penetrating implement need not retract. Thus, movement of theimplement between its retracted and advanced conditions, in such cases,need only involve movement of the implement move from its retracted toits advanced condition.

[0066] In another embodiment of the present invention, a selectedtherapeutic and/or diagnostic agent comprising a charged species (forexample, DNA) is held within the distal-end region of an accessingdevice and delivered into a cavity formed by in a selected tissue via anelectrical field. An exemplary cavity-forming and delivery implement,which can be incorporated in a catheter-type tool or an endoscope-type,such as previously described, is shown in FIGS. 7A-7C. Here, theimplement includes drug-delivery reservoir or storage vessel 114 whichopens into the region between a plurality of expandable members 116 viashort passage 118 through a neck member 120. First and second leadwires, denoted as 122 and 124 respectively, extend through a flexibleactuation accessing device 126 and terminate at respective terminals, orelectrodes, fixed in the implement. The first terminal, indicated as123, being placed at a rearward (proximal) region of the vessel 114, andthe second terminal, denoted as 125, being placed at a forward (distal)region of the implement's cutting/slicing tip 128. In an exemplaryoperation, whereby DNA, indicated as 130, is delivered into myocardialtissue 132 of a subject, the catheter accessing device 134 is introducedinto a subject body and placed against an endocardial or epicardial wall136 of the heart's left ventricle (FIG. 7A). During such introductionand placement, the vessel terminal 123 is made positive (+) and the tipterminal 125 is made negative (−), thereby establishing an electricalfield that maintains the negatively charged DNA in the vessel 114. Itshould be noted that the lead wires 122, 124 and regions about theterminals 123, 125 are shielded, using conventional materials, to limitthe field's reach into the surrounding heart tissue. Such shieldingabout the forward (distal) region of the implement is indicated byback-hatching in the drawings. After placement of the catheter,actuation accessing device 126 is advanced, via a remote shiftingmechanism (such as previously described), to push the slicing tip 128through the wall 136 and into a region of myocardium 132, with theexpandable members 116 following the tip therein. Once a cavity has beenformed in the myocardium, the polarity is reversed, so that the tipterminal 128 is positive (+) and the vessel terminal 123 is negative (−)(FIG. 7B), thereby establishing an electrical field effective to drawthe negatively charged DNA 130 toward the tip 128. After a short time,with at least a substantial member of the DNA drawn out of the vessel114, the electrical field is discontinued (FIG. 7C), so that the DNA canmove outwardly into the surrounding tissue and capillaries of themyocardium.

[0067] In another embodiment, a selected therapeutic and/or diagnosticagent is held within the distal-end region of an accessing device andplaced in a cavity formed in a selected tissue. An exemplarycavity-forming and placement implement, which can be incorporated in acatheter-type tool or an endoscope-type, such as previously described,is shown in FIGS. 8A-8C. Here, the implement includes a plurality ofexpandable members 142 attached at their rearward (proximal) ends to aflexible actuation accessing device 144, and at their forward (distal)ends to a cutting/slicing tip 146. The expandable members 142 arearranged to serve as a cage or skeleton for containing a selected agent148, in solid or semi-solid form, as the catheter accessing device 150is placed against a selected organ wall, as at 152 (FIG. 8A). Actuationaccessing device 144 is then advanced, via a remote shifting mechanism,to push the slicing tip 146 of the implement through the wall 152 andinto a selected layer of tissue 154, with the expandable members 142following the tip 146 therein (FIG. 8B). Once a cavity has been formedin this manner, the agent 148 is allowed to move outward into thesurrounding tissue and capillaries (FIGS. 8B-8C). The agent can beconfigured to for controlled release after placement, for example, viaswelling and sloughing over a period of several minutes. In oneembodiment, wherein the agent is DNA, controlled-release preparationsare formulated through the use of polymers to complex or absorb theselected gene sequence (with or without an associated carrier, forexample, liposomes, etc.). The agents can be formulated according toknown methods to prepare pharmaceutically useful compositions, wherebythese materials, or their functional derivatives, are combined inadmixture with a pharmaceutically acceptable carrier vehicle. Suitablevehicles and their formulation, are described, for example, in Nicolau,C. et al. (Crit. Rev. Ther. Drug Carrier Syst 6:239-271 (1989)), whichis incorporated herein by reference. In order to form a pharmaceuticallyacceptable composition suitable for effective administration, suchcompositions will contain an effective amount of the desired genesequence together with a suitable amount of carrier vehicle.

[0068]FIG. 9a depicts a preferred embodiment of the invention whereaccessing device 900 further comprises force contact transducer 902mounted on distal end 904 of accessing device 900. As accessing device900 is urged toward tissue 906, as shown in FIG. 9b, force contacttransducer 902 contacts tissue 906 causing detectable contact pressureto develop between force contact transducer 902 and tissue 906. Suchdetectable pressure, detected by force contact transducer 902 iscommunicated back to the end user who then can further manipulateaccessing device 900 to achieve perpendicularity between the thrust axisof accessing device 900 and tissue 906. Upon achieving perpendicularityand contact force, tissue-penetrating implement 908, with cutting tip908 a, may be advanced to an extended condition, from a retractedposition, thus causing the formation of cavity 910 in tissue 906.Because accessing device 900 is urged against tissue 906 in aperpendicular manner, distal end 904 of accessing device 900 develops aseal for sealing in later delivered drug into cavity 910. FIG. 9cdepicts accessing device 900 without force contact transducer 902. FIG.9c suggests how a non-perpendicular orientation of accessing device 900with respect to tissue 906 could result in seepage of delivered drug 912from cavity 910. FIG. 9d further depicts accessing device 900 withoutforce contact transducer 902 urged against tissue 900. Tissue 900 isfurther depicted in two states, diastolic state tissue 906a and systolicstate tissue 906 b correlating to the movement of myocardial tissue in abeating heart. As shown in FIG. 9d, diastolic position tissue 906 aprovides a seal between tissue 906 and accessing device 900. However,upon systolic movement, tissue 906 moves away from accessing device 900unless sufficient contact force exists between accessing device 900 andtissue 906. Force contact transducer 902 provides information to theuser to enable the user to apply sufficient and perpendicular force tothe accessing device to create a seal between accessing device 900 andtissue 906 during the movements of beating heart between tissue 900 aand 900 b states. Moreover, FIG. 9d depicts how delivered drug 912 maybe further ejected or pumped out of cavity 910 by the contractileactions between heart tissue 900 a and 900 b states.

[0069]FIG. 10 depicts another embodiment of the invention utilizingcorkscrew shaped tissue-penetrating implement 1000. Accessing device1002 houses tissue-penetrating implement 1000 that may be rotated withinaccessing device in either a retracted condition or an extendedcondition. FIG. 10a depicts tissue-penetrating implement 1000 securedinto tissue 1004 by screwing. As tissue-penetrating implement 1000 iswithdrawn back towards a retracted condition, tissue 1004 is likewisepulled into lumen 1006 of accessing device 1002 thus creating seal 1006between accessing device 1002 and tissue 1004. Such pulling furthercreates cavity 1008 at distal end 1010 of tissue-penetrating implement1000. Cavity 1008 may then be filled with delivered-drug, not shown,delivered through lumen orifice 1012 to treat the walls of cavity 1008with such drug.

[0070]FIG. 11 depicts another embodiment of the invention where theexpandable members comprise a balloon structure with drug-delivery lumenorifices distributed along the surface of the expandable members. FIGS.11a and 11 b depicts a tissue-penetrating implement 1101 comprising fourradially distributed expandable members 1100 defining lumens 1102 withexit ports 1104 outwardly situated on balloon 1106. Penetrating tip 1108is situated on the end of the balloon distal from accessing device 1110,not shown. As balloon 1106 is inflated, expandable members 1100 areurged outward against the tissue of a cavity, not shown. FIG. 11cfurther shows yet another embodiment using a balloon as an expandablemember and drug-delivery channel. Accessing tool 1110 is urged againsttissue 1112, whereby tissue-penetrating implement 1101 comprises aballoon expandable member 1106 with distally situated exit ports 1104and penetrating or cutting tip 1108.

[0071]FIG. 12 depicts a preferred embodiment of the invention wheretissue penetrating implement 1200 comprises at least one firstexpandable member 1202 made from a shape memory material compositionhaving a first remembered arc shape and a second, stress induced,straight shape. First expandable member 1202 assumes a stress inducedstraight shape when housed within lumen 1204 of accessing tool 1206, butreturns to its remembered shape upon extension beyond lumen 1204. Asfirst expandable member 1202 extends from lumen 1202, it cuts an arcshaped path through tissue 1210 as first expandable member 1202 regainsits remembered shape. Tissue-penetrating implement 1200 has cutting tip1208 situated distal to accessing tool 1206 for cutting tissue 1210 astissue-penetrating implement 1200 is advanced into tissue 1210 whenadvanced from a retracted condition to an extended condition out oflumen 1204. Second expandable member 1211 extends from lumen 1204coaxial to first expandable member 1202. Adjacent tissue-penetrationimplement's distal end, first and second expandable members arepositioned together either fixedly or slidably. When fixedly positioned,both expandable members 1202 and 1211 extend together, but expandlongitudinally from one another to form cavity 1212. When first andsecond expandable members 1202 and 1211 are slidably positioned, theuser may either extend one expandable member, preferably the firstexpandable member 1202 having cutting tip 1208, and then extend secondexpandable member 1211 to follow along cut path 1216 created bypreviously extended first expandable member 1202, expandinglongitudinally away from first expandable member 1202 to create cavity1212 where a drug may be infused from a drug-delivery reservoir, notshown, in fluid communication through a conduit with the distal regionof accessing device 1222. FIG. 12b depicts a variation where secondexpandable member further comprises construction from shape memory tube1218, such as nitinol or NiTi tubing, defining a longitudinal lumen influid communication with a drug-delivery reservoir, not shown, andterminating with exit ports 1220 adjacent to the distal end of secondexpandable member. During or after the formation of cavity 1212, drugmay be delivered from the drug-delivery reservoir, not shown, to thecavity 1212 through the lumen and exit ports 1220 of second expandablemember 1211. FIG. 12c depicts a variation where first and secondexpandable members 1202 and 1211 are spaced-apart from one another by,for example, having two lumens, not shown, defined within accessingdevice 1222. Force contact transducer 1224 is located on the distal endof accessing device 1222 to assist a user in achieving the sufficientand perpendicular contact force with respect to tissue 1210 to create aseal between tissue 1210 and the distal end of accessing device 1222.One skilled in the art would readily recognize the benefits of the abovementioned embodiment. In particular, the presence of second expandablemember 1211 made from a shape memory material that assumes a stressinduced straight shape when housed within lumen 1204 of accessing tool1206, but returns to its remembered shape upon extension beyond lumen1204, when configured as shown in FIG. 12, provides the ability toshepherd first expandable member 1202 further in its arc shape cuttingpath by applying lateral force to cutting tip 1208 as it cuts throughtissue 1210. This further prevents cutting tip from accidentally cuttingtoo deep through a wall like tissue and thus perforating the wall andturning a cavity into a passage.

[0072] Additional pharmaceutical methods may be employed to control theduration of action. Controlled delivery may be exercised by selectingappropriate macromolecules (for example polyesters, polyamino acids,polyvinyl, pyrrolidone, ethylenevinylacetate, methylcellulose,carboxymethylcellulose, or protamine, sulfate) and the concentration ofmacromolecules as well as the methods of incorporation in order tocontrol release. Another method to control the duration of action bycontrolled release preparations is to incorporate the agent intoparticles of a polymeric material such as polyesters, polyamino acids,hydrogels, poly(lactic acid) or ethylene vinyl acetate copolymers.Alternatively, instead of incorporating these agents into polymericparticles, it is possible to entrap these materials in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose or gelatinmicrocapsules and poly(methylmethacylate) microcapsules, respectively,or in colloidal drug delivery systems, for example, liposomes, albuminmicrospheres, microemulsions, nanoparticles, and nanocapsules or inmacroemulsions.

[0073] The drug-delivery tool and method of the present invention mayemploy a wide variety of agents, for example, ranging from activecompounds to markers to gene therapy compounds. Exemplary agents,contemplated for use herein, are set forth in U.S. Pat. Nos. 5,840,059;5,861,397; 5,846,946; 5,703,055; 5,693,622; 5,589,466; and 5,580,859,each expressly incorporated herein by reference. In one embodiment, forexample, the invention is employed to deliver one or more genes (forexample, as so-called “naked DNA”) into cavities formed in themyocardium of a subject.

[0074] In appropriate situations, the agent can be delivered in a formthat keeps the agent associated with the target tissue for a usefulperiod of time, such as with a viscosity-enhancer to produce athixotropic gel. In certain embodiments, the therapeutic or diagnosticagent is mixed with a viscous biocompatible polyol to maintainprolonged, high concentration of the agent in the channels and affectthe kinetics of the agent-target region interaction.

[0075] Alternatively, a catheter could be employed to deliver an agentincorporated in a biocompatible polymer matrix. Suitable polymericmaterials are known in the art, for example, as set forth in U.S. Pat.No. 5,840,059, incorporated herein by reference. For example,non-biodegradable polymers can be employed as hollow reservoirs or otherstructures. Additionally, conventional pharmacologically inert fillersmay be employed to tailor the time release characteristics of the agent.Certain embodiments contemplate the use of biodegradable polymers, suchas collagen, polylactic-polyglycolic acid, and polyanhydride. Forexample, the agent can be dispersed in a polymer which is configured todegrade over a useful period of time, releasing the agent. In oneembodiment, the agent is released by swelling and sloughing of thebiodegradable polymer. Various means for employing polymer compounds tosecure a therapeutic agent are disclosed, for example, in Levy et al.,WO 94/21237 and in U.S. application Ser. No. 08/033,307, filed Mar. 15,1993, which is hereby incorporated by reference. In still otherembodiments, a biocompatible material is delivered to seal and retainthe agent within the cavity. For example, a delivery lumen could beemployed to deliver a sealing agent after delivery of the agent.

[0076] Those skilled in the art can now appreciate from the foregoingdescription that the broad teachings of the present invention can beimplemented in a variety of forms. Therefore, while this invention hasbeen described in connection with particular embodiments and examplesthereof, the true scope of the invention should not be so limited.Various changes and modification may be made without departing from thescope of the invention, as defined by the appended claims. For example,the expandable members of the tissue-penetrating implement can beconfigured not to expand, but rather to maintain a substantiallyconstant configuration as it is moved between its retracted and advancedconditions. By this construction, the cage or skeleton structure definedby the expandable members can serve, when inserted into a tissue, tohelp form a temporary cavity, and maintain the cavity as one or moreselected agents are delivered and/or drawn therein. Thus, while anexpandable member (as described above) is advantageous for manypurposes, a non-expandable cage or skeleton in place of the previouslydescribed expandable member can provide useful advantages, as well.

It is claimed:
 1. A drug-delivery tool for delivering a drug to aninternal member of a tissue, such as a heart-wall, comprising: (a) anaccessing device having distal and proximal ends, an inner lumenextending therebetween, a drug-delivery reservoir adapted to hold suchdrug, and user-control structure at the accessing device's proximal end,(b) a tissue-penetrating implement carried at the accessing device'sdistal end for axial movement into and out of the lumen, the implementhaving first and second expandable members which are disposed in asubstantially co-extension condition, when the implement is disposed ina retracted condition within the lumen, and an expanded, spaced-apartcondition when the implement is advanced to an extended condition out ofthe lumen, at least one of the members having a tip for penetrating suchtissue, (c) a first operative connection between the control structureand the implement which is operable, upon user activation of the controlstructure, to advance the implement from its retracted to its extendedcondition, wherein, with the accessing device's distal end placedagainst a surface region of the tissue, the implement is advanced intothe tissue, causing the two expandable members to expand to form acavity within the tissue, and (d) a second operative connection betweenthe control structure and the reservoir which is operable, upon useractivation of the control structure, to deliver drug from the reservoirinto such cavity, wherein placement of the accessing device's distal endagainst a surface region of such tissue, and activation of the controlstructure results in the delivery of drug into a cavity within thetissue.
 2. The tool of claim 1, wherein the implement includes at leasttwo expandable elements which move away from one another as theimplement is being advanced, from its retracted to its extendedcondition, into such tissue, to form a cavity in the tissue.
 3. The toolof claim 1, wherein the second expandable member of thetissue-penetrating implement defines a lumen having a plurality ofopenings that permit direct communication of an drug passed into acavity formed by the tool with at least about 90% of the surface area ofthe tissue directly bordering the drug receiving space.
 4. The tool ofclaim 1, wherein the accessing device is a flexible catheter accessingdevice; and further comprising (i) a pull-wire assembly extendinglongitudinally through the catheter accessing device, the pull-wireassembly being operable to deflect the distal end of the accessingdevice substantially within a plane; and (ii) one or more force contacttransducers mounted at the distal end of the accessing device within thedeflection plane.
 5. The tool of claim 4, further comprising one or moreadditional force contact transducers mounted at the distal end of theaccessing device outside of the deflection plane.
 6. The tool of claim1, wherein the accessing device is incorporated in an endoscopeassembly.
 7. The tool of claim 1, wherein the tissue-penetratingimplement includes (i) a cutting or slicing tip on the first expandablemember, and (ii) one or more resiliently flexible second expandablemembers being adapted to expand radially outward in their normal state.8. The tool of claim 1, wherein a drug-delivery passage is formed by anelongate conduit having an internal lumen that extends betweentissue-penetrating implement and drug-delivery reservoir; the conduitbeing adapted for sliding movement within the accessing device, coupledwith movement of the tissue-penetrating implement.
 9. The tool of claim8, for use in delivering a selected drug having a net negative charge,further comprising first and second electrodes adapted to be placed inelectrical communication with a power supply, with the first electrodebeing disposed at a distal region of the tissue-penetrating implementand the second electrode being disposed proximally of thetissue-penetrating implement; wherein generation of a positive charge atthe first terminal is effective to draw at least a member of thenegatively charge species from the drug-delivery passage into theexpandable members of the tissue-penetrating implement.
 10. The tool ofclaim 1, for use with solid or semi-solid agents, wherein the secondexpandable member of the tissue-penetrating implement comprises aplurality of resiliently flexible expandable members disposed at spacedpositions about the longitudinal axis of the tool so as to define a cageor skeleton capable of holding such an agent as it is placed in a cavityformed by the implement.
 11. The tool of claim 1, wherein at least oneof the expandable members has a tissue-penetrating tip, and at least oneof the expandable members has a cutting tip for slicing tissue in thedirection of expansion of the implement members, to produce adrug-receiving for the which move away from one another as the implementis being advanced into such tissue, from its retracted to its extendedcondition, to form a drug-receiving pocket in the tissue.
 12. The toolof claim 1, 3, 2, 4, or 5, wherein the first expandable member furthercomprises construction from a shape memory material capable of a firstremembered curved shape, and a second, stress induced linear shapecausing the first expandable member to cut in an arc shape as it isadvanced through a tissue.
 13. The tool of claims 1, 2, 4, or 5, whereinthe second expandable member comprises a ribbed balloon, wherein eachrib defines a lumen in communication with the drug-delivery reservoir,and each rib further defines a plurality of exit ports from the riblumen that the drug may perfuse through into the formed cavity.
 14. Thetool of claims 1, 2, 4, or 5, wherein the first expandable member isformed in a cork-screw shape tubular member defining a lumen withinexiting at an end distal to the accessing device and in communicationwith the drug-delivery reservoir, the first expandable member isrotatable along its axis to permit it to screw into a tissue upon axialrotation, and upon stopping axial rotation, withdraw into the lumen ofthe accessing device thereby pulling the tissue up into the lumen of theaccessing device until such tissue is sealably urged against theaccessing implement's lumen edge causing a seal to form between theaccessing implement's lumen edge and the tissue, and further causing acavity to form between the distal region of the first expandable memberand the tissue adjacent to that region.
 15. A method for delivering aselected diagnostic or therapeutic agent to a target site within aselected body tissue, comprising: (i) forming a cut or slice extendingfrom a wall of the selected tissue to the target site; (ii) moving thetissue bordering the cut or slice radially outward, thereby forming acavity within the tissue at the target site; (iii) delivering a selectedagent into the cavity; and (iv) permitting the cavity to collapse once aselected amount of the agent has been delivered therein.
 16. The methodof claim 15, wherein step (i) is effected using a cutting or slicingimplement that is configured to avoid the removal of tissue along theregion of the cut or slice beyond the inherent cellular injury due tothe cutting or slicing.
 17. The method of claim 15, wherein theimplement is a blade edge or tip.
 18. The method of claim 15, whereinthe cut or slice formed in step (i) is made along a substantially linearaxis, with the axis being oriented generally normal to the wall of theselected tissue.
 19. The method of claim 16, wherein the agent isdelivered using an elongate agent-delivery conduit defining a passage orlumen terminating at a distal orifice through which the agent can exit;and wherein, during delivery of the agent, the orifice does not makesubstantial contact with the selected tissue, thereby maximizing thetissue surface area available for contact with the agent.
 20. The methodof claim 15, wherein the selected tissue is heart tissue, and the cut orslice is formed from an endocardial wall, a septal wall, or anepicardial wall.
 21. The method of claim 18, wherein the selected tissueis myocardial tissue, and the selected agent includes a species havingangiogenic properties.
 22. The method of claim 15, wherein the selectedtissue is myocardial tissue, and the selected agent includes a nucleicacid.
 23. The method of claim 15, wherein the selected tissue isstunned, ischemic or hibernating organ tissue that has at leastpartially lost its normal capillary ability at natural vasomotion. 24.An drug-delivery tool for delivering a selected diagnostic ortherapeutic agent to a target site within a selected body tissue,comprising: an accessing device having proximal and distal ends, with alumen extending between said ends and terminating at an orifice at saiddistal end; a tissue-penetrating implement movable between a retractedcondition, within a distal region of said lumen, and an extendedcondition, extending out of said orifice; wherein said implementincludes (i) a tip configured to penetrate a selected body tissue whenthe distal end of the accessing device is placed thereagainst and theimplement is moved from its retracted condition to its extendedcondition, and (ii) an expandable member disposed proximal of said tipfor following the tip to a target site within such tissue, and adaptedto expand radially, with the implement at its extended condition, withsufficient force to form a cavity at the target site by pressing thetissue at the target site away from the longitudinal axis of theimplement; and an agent-delivery passage extending longitudinallythrough at least a member of said accessing device, with a distal end ofsaid passage defining an exit port facing said expandable member fordirecting a selected agent, passed through the passage, into a centralregion of the expandable member and any such cavity formed thereby. 25.The drug-delivery tool of claim 24, wherein said expandable member ofsaid tissue-penetrating implement defines a plurality of openings thatpermit direct communication of an agent passed into a cavity formed bysaid implement with at least about 90% of the surface area of the tissuedirectly bordering the cavity.
 26. The drug-delivery tool of claim 24,wherein the accessing device is a flexible catheter accessing device;and further comprising (i) a pull-wire assembly extending longitudinallythrough said catheter accessing device, said pull-wire assembly beingoperable to deflect a distal-end region of said accessing devicesubstantially within a plane; and (ii) one or more ultrasoundtransducers mounted at the distal end of the accessing device withinsaid deflection plane.
 27. The drug-delivery tool of claim 26, furthercomprising one or more additional ultrasound transducers mounted at thedistal end of the accessing device outside of said deflection plane. 28.The drug-delivery tool of claim 24, wherein the accessing device isincorporated in an endoscope assembly.
 29. The drug-delivery tool ofclaim 24, wherein the tissue-penetrating implement includes (i) acutting or slicing tip at its distal-end region, and (ii) one or moreresiliently flexible expandable members extending proximally therefrom,with said expandable members being adapted to expand radially outward intheir normal state.
 30. The drug-delivery tool of claim 29, furthercomprising an actuation line attached to a proximal end of saidimplement and extending to the proximal end of said accessing device,with said line being adapted for sliding movement within said accessingdevice; whereupon movement of said accessing device effects movement ofsaid implement.
 31. The drug-delivery tool of claim 24, wherein saidagent-delivery passage is formed by an elongate conduit having aninternal lumen that extends between the proximal end of the accessingdevice and a distal-end region of the accessing device; said conduitbeing adapted for sliding movement within said accessing device, coupledwith movement of said tissue-penetrating implement.
 32. Thedrug-delivery tool of claim 24, for use in delivering a selected agenthaving a net negative charge, further comprising first and secondelectrodes adapted to be placed in electrical communication with a powersupply, with the first electrode being disposed at a distal region ofsaid tissue-penetrating implement and the second electrode beingdisposed proximally of the implement; wherein generation of a positivecharge at said first terminal is effective to draw at least a member ofthe negatively charge species from the agent-delivery passage into theexpandable member of the tissue-penetrating implement.
 33. Thedrug-delivery tool of claim 24, for use with solid or semi-solid agents,wherein said expandable member of said tissue-penetrating implementcomprises a plurality of resiliently flexible expandable membersdisposed at spaced positions about the longitudinal axis of theimplement so as to define a cage or skeleton capable of holding such anagent as it is placed in a cavity formed by the implement.
 34. Andrug-delivery tool for delivering a selected diagnostic or therapeuticagent to a target site within a selected body tissue, comprising: (i) anaccessing device having proximal and distal ends, with a lumen extendingbetween said ends and terminating at an orifice at said distal end; (ii)a tissue-penetrating implement movable between a retracted condition,within a distal region of said lumen, and an extended condition,extending out of said orifice; wherein said implement includes (i) a tipconfigured to penetrate a selected body tissue when the distal end ofthe accessing device is placed thereagainst and the implement is movedfrom its retracted condition to its extended condition, and (ii) a cagemember disposed proximal of said tip for following the tip to a targetsite within such tissue, and adapted to assist in the formation andmaintenance of a cavity at the target site by pressing the tissue at thetarget site away from the longitudinal axis of the implement as it isinserted therein and having sufficient rigidity to resist inwardlydirected forces of the tissue tending to collapse the cavity; and (iii)an agent-delivery passage extending longitudinally through at least amember of said accessing device, with a distal end of said passagedefining an exit port facing said cage member for directing a selectedagent, passed through the passage, into a central region of the cagemember and any such cavity formed thereby.
 35. A method for delivering aselected diagnostic or therapeutic agent to a target site within aselected body tissue, comprising: (iv) forming a cut or slice extendingfrom a wall of the selected tissue to the target site; (v) moving thetissue bordering the cut or slice radially outward, thereby forming acavity within the tissue at the target site; (vi) delivering a selectedagent into the cavity; and (vii) permitting the cavity to collapse oncea selected amount of the agent has been delivered therein.
 36. Thedrug-delivery tool of claim 34, wherein at least 90% of the surface areaof the tissue bordering the cavity is directly exposed to the cavity, sothat an agent delivered into the cavity can pass directly into theexposed tissue.
 37. The method of claim 35, wherein step (i) is effectedusing a cutting or slicing implement that is configured to avoid theremoval of tissue along the region of the cut or slice beyond theinherent cellular injury due to the cutting or slicing.
 38. The methodof claim 35, wherein the implement is a blade edge or tip.
 39. Themethod of claim 35, wherein the cut or slice formed in step (i) is madealong a substantially linear axis, with the axis being orientedgenerally normal to the wall of the selected tissue.
 40. The method ofclaim 35, wherein the agent is delivered using an elongateagent-delivery conduit defining a passage or lumen terminating at adistal orifice through which the agent can exit; and wherein, duringdelivery of the agent, the orifice does not make substantial contactwith the selected tissue, thereby maximizing the tissue surface areaavailable for contact with the agent.
 41. The method of claim 35,wherein the selected tissue is heart tissue, and the cut or slice isformed from an endocardial wall, a septal wall, or an epicardial wall.42. The method of claim 35, wherein the selected tissue is myocardialtissue, and the selected agent includes a species having angiogenicproperties.
 43. The method of claim 35, wherein the selected tissue ismyocardial tissue, and the selected agent includes a nucleic acid. 44.The method of claim 35, wherein the selected tissue is stunned, ischemicor hibernating organ tissue that has at least partially lost its normalcapillary ability at natural vasomotion.
 44. The tool of claim 1,wherein the accessing device is incorporated in an open surgicalassembly.